The Biology of Depression

There's a lot to be said about the biology of depression, explained today in Dr Robert Sapolsky's overview of the genetics, neurochemistry and psychology of depression.

There are a lot of terrible diseases out there. Elephant man disease, prion disease, dying of old age at 11 disease. But if you want the creme-de-la-creme of human misery, you can't do better than depression. It's hands-down the worst disease you can get.

Depression is depressingly common. As much as 15% of people will experience major depression in their lives, no matter where they live in the world. It's the #4 cause of disability, predicted to jump to #2 by 2025, after obesity and diabetes-related disorders.

Many people don't understand depression as an illness - which is why it's common to go undiagnosed for months or years - let alone the biological connection. Consider the different levels at which people refer to depression in their everyday language.

1. Your car breaks down and you miss out on an evening with friends you had been looking forward to all week. "Oh my god, tonight was so depressing." That is not the depression we are talking about.

2. Your girlfriend breaks up with you after a five-month relationship, and you feel rejected and sad for a few days or weeks. But time heals and you eventually come out the other end feeling happy again. This is reactive depression, in response to a negative event.

3. Your everyday life has become chronically stressful - or the opposite, chronically empty. Everyday life provides few positive feedback loops to sustain your peace of mind and you feel highly anxious, or altogether flat and hopeless. This is major depression.

What is Depression?

According to Dr Robert Sapolsky, whose Stanford lecture on the biology of depression is the foundation of this article, "depression is a biochemical disorder with a genetic component and early experiential influences which means you can't enjoy sunsets anymore".

Take a disease like cancer. Even after facing their own mortality, cancer survivors often say things like "if I never had cancer, I would never have reconnected with my brother/sister/parent". They're able to see the silver lining of enduring adversity.

This doesn't happen with depression. In its grip, you can be sharing a beautiful sunny day with your loved ones but the depression steals any possibility of enjoyment. Whatever the experience, your overwhelming reaction is fear, anxiety, hopelessness, or numbing ambivalence.

It's also a lingering disease, threatening you with relapse, so even after you've lifted yourself out of the depths of depression, you never feel completely free of it.

The Symptoms of Depression

Anhedonia is the inability to feel pleasure. It's a hallmark of depression and is what makes it the worst disease imaginable. What's the point of living if you never feel okay? Worse than that: if every sunset and social event and creative expression is laden with hopelessness? These aren't maudlin gestures but powerful biologically driven emotions which define your life.

In depression, grief and guilt can take a delusional quality. We might obsess about something we did to someone a decade ago, and which may be unfixable or completely redundant because that person has long since moved on with their life. Or we can generate delusional thoughts relating to events in the present.

Sapolsky gives us an example of a 50-year-old engineer who has a heart attack. He's admitted to hospital and the doctors say he has to make some changes to his lifestyle but he's going to make a good recovery. These were scary times, but the outlook is positive for the man. But instead of writing a new bucket list, he falls into a major depression. The world has lost its colour and he feels utterly hopeless about the future.

"You're improving," his family say encouragingly on their hospital visits. "Yesterday you walked one lap around the ward, and today you walked two laps." But the depressed man manages to twist this into a negative. "No. They're doing renovations in the hospital. They closed some corridors. Two laps today is actually less than one lap yesterday." Not only is this untrue, making the man delusional, but he actually finds a way to convince himself using his background in structural engineering. He continually seeks ways to prove the future is bleak, in alignment with the way his neurochemistry is making him feel.

Let's remember this behaviour makes sense. If you have a crippling sharp pain in your right foot, you stop and take a good look for the Lego brick you might have just stepped on. You seek ways of explaining the cause of the pain.

If delusional grief is not enough, let's add self-injury, self-mutilation and suicide to the list of depression symptoms. It makes little sense from the outside, but to the sufferer of depression, these behaviours promise to relieve the agonising emotional pain. Suicide (along with car accidents) is the leading cause of death in teenagers and young adults. They're among the most vulnerable people in terms of undiagnosed and untreated depression.

Now take psychomotor retardation. Everything is exhausting when your motivation for living is at absolute zero. The idea of a single chore like doing the washing is a long road to nowhere. You have to get the basket... the laundry detergent... change for the machine... it's too much. This is not the stage when you worry about suicide. Someone who is catatonic, or too exhausted to get out of bed isn't going to shred the sheets to make a noose.

It's when they come out of psychomotor retardation they are at highest risk of suicide.

Just Snap Out Of It

We all feel sad and withdrawn at times. But then we get a good night's sleep, or have a long talk with a friend, or make some big life decisions. And we cope.

So why can't a depressed person come out the other side?

Sapolsky argues that depression is fundamentally a biological condition, like a stroke or a heart attack. If you have major depression, the causes of your illness are physically inside your body and they need to be fixed, physically, before your psychology and outward behaviours can change.

In minor depression, you may experience patterns of sleeplessness and insomnia, causing you to lay awake, tossing and turning at night, your mind buzzing with unresolved thoughts. This contrasts with major depression, where you wake up early, say 3am, and can't get back to sleep no matter how exhausted you feel. Brain scans of depressives reveal their sleep phases are completely disordered. This is a biological symptom.

Minor depressives also tend to comfort eat more, which is logical because carbohydrates are shown to decrease the release of stress hormones. Major depressives, on the other hand, don't feel anything and so find no comfort in food. They have a significantly decreased appetite. The scorned rom-com starlet who sits sobbing into a jumbo tub of octuple-choc ice cream is not displaying symptoms of major depression.

When looking at someone who is mired in psychomotor retardation and unable to get out of bed, it's tempting to see them as lazy. In fact, their sympathetic nervous system is overactivated. They're blasting through stress hormones in an epic internal battle. Stress responses, such as the spike of anger we may experience when someone cuts us off in traffic, are sustained and constant in the body of a major depressive. This is not psychology: round-the-clock adrenaline isn't a state you can create with your mind alone. This is biology.

Major depression often has a rhythmic pattern. Some sufferers have shown two months of extreme symptoms before coming out the other side. Then, 18 months later, they undergo another two months of depressive symptoms before they come out the other end. Then, 18 months later, the cycle repeats again.

Some people only suffer from depression during winter, known as Seasonal Affective Disorder (SAD). A person with SAD may experience a horrible event in the summer, go through the appropriate amount of reactive depression, then recover quickly. But come winter, something relatively minor happens, like they get into an argument at work, they get barked at by a dog, or a chicken looks at them funny, and they fall into a state of such sadness that they can't get out of bed for two months.

The Neurochemistry of Depression

When you talk to someone, you use your lungs to push air through your larynx, you shape the sound waves into words with your mouth, and the sound of your voice is transduced by their cochlea and interpreted by their brain.

When neurons talk to each other, they release a chemical messenger (a neurotransmitter) into a gap called a synapse. The neuron has a big balloon filled with neurotransmitters, so when the excitation signal comes along it releases some of those neurotransmitters into the gap. The neurotransmitters bind to a receptor, then something changes in the other neuron.

There are hundreds of types of neurotransmitters, but only a few (that we know of) are relevant in depression.

The first is norepinephrine (pronounced nora-pin-EFF-rin) which is generally associated with mobilising the body and brain for action. Norepinephrine first became implicated in depression in the early 1960s, and lead to the first wave of antidepressants called monoamine oxidase inhibitors, or MAOIs.

There are two ways of getting rid of all the neurotransmitters floating around in the synapse. You can recycle them and put them back into the bag, this is called reuptake. Or you can throw them out by breaking them down with enzymes, and flush them out with your urine. The enzyme that breaks down norepinephrine can be slowed down by the MAOI antidepressants. The result is that the neurotransmitters stay in the synapse longer, and suddenly depression goes away.

In the late 1960s another class of antidepressants came in, called tricyclic antidepressants. They gum up the pump that recycles the norepinephrine, so it sits around in the synapse with nothing to do, and decides to hit the receptor again. So the same amount of norepinephrine ends up hitting the receptor several times and depression goes away.

It's interesting to note that there's a particular type of drug called Reserpine that actually decreases your norepinephrine release. But why would you want to do this? It's not a treatment for depression - rather, it's main affect is to reduce blood pressure - but one possible side effect of Reserpine is it causes depression. This observation provides more convincing evidence for the norepinephrine hypothesis of depression.

What Does Norepinephrine Do To The Brain?

Scientists figured this out in the 1950s, and it has a lot to do with that anhedonia thing that we mentioned earlier. It turns out, if you put an electrode in a rat's brain to stimulate the release of norepinephrine, it makes the rat unbelievably, ridiculously, insanely happy.

How do you know a rat's happy?

You make him work to get the thing that makes him happy. Get a rat to push a lever 25 times to get a hit of that delicious norepinephrine. A rat will push that lever all day. It's better than food, or sex, or drugs; they will choose the lever every time. They will push that lever until they starve to death.

The same thing is seen in humans. The beauty of tampering with people's brains is you don't need to anaesthetise them because the brain doesn't feel pain. The patient can be awake while you fiddle with their grey matter, all the while talking to them and asking them questions about how they feel.

Here's a non-exhaustive list of things which stimulate norepinephrine:

Having sex

Scratching an itch

Playing in the leaves after dinner on a warm evening

Eating cookies in winter

Making a witty retort to a negative Youtube comment

So clearly a shortage of norepinephrine explains anhedonia.

Or does it?

There are two problems with the theory that norepinephrine deficiency leads to depression.

Norepinephrine vs Dopamine vs Serotonin

If you throw a few MAOIs or tricyclic antidepressants into a person, it makes a difference to their norepinephrine levels in the space of hours. However the depressed person won't notice any difference for weeks. Something's not working here.

"Wait!" I hear you shout. "That's just one problem! You clearly wrote there are two problems with the norepinephrine theory! I am angry!"

Good point. Ok here's the second problem. It turns out while norepinephrine is involved in the pleasure pathway, another neurotransmitter turns out to be even more important to happiness: dopamine.

While norepinephrine is stimulated by exercise and cookies, dopamine is boosted by cocaine. Personally I've never sampled the apparent delights of cocaine but I hear it's pretty good for a few minutes. Life-wreckingly good. So norepinephrine is only a part-time player when it comes to the feeling of achievement and well-being.

Fast forward to the bangin' 1980s. The drug known as Prozac came about, promising to be the real deal for depression deflection. Prozac was the first of its class of drugs called selective serotonin reuptake inhibitors, or SSRIs. This drug works on a completely different neurotransmitter called serotonin, by increasing serotonin signalling. When you increase serotonin, depressed people feel better, so it looks like the major depressive has too little serotonin.

This leads to huge fights between the serotonin, norepinephrine and dopamine gangs.

"Hey. I didn't come here to learn what ISN'T the biology of depression, I came here to learn what IS!"

In short, the best evidence so far is a lack of all three neurotransmitters correlate to different but synergetic symptoms of depression. Simplistically put, anhedonia is related to a lack of dopamine. Psychomotor retardation is a lack of norepinephrine. And an obsessive sense of grief or guilt is caused by a lack of serotonin. The latter is supported by the observation that obsessive compulsive disorders are relieved by serotonin-related SSRIs.

Now, just for fun, let's introduce another neurotransmitter called Substance P. Sub-P is about pain. Stand on a Lego brick and your spinal neurons release sub-P. Scientists have long known that if depressives are given a drug that reduces sub-P signalling, they sometimes get better. What the hell? This shows your body is using the same brain chemistry in depression as is seen in real physical pain. This is yet more evidence that biology - not psychology - drives major depression.

Neuroanatomy and Depression

To get a background of the neuroanatomical story of depression, we need to refer to the triune brain model. This defines three parts of the human brain:

The hindbrain

The midbrain (aka the limbic system)

The forebrain (aka the cortex)

The hindbrain is the lower part of the brain, which was the first part to evolve. It does a lot of different things, including the most critical of body functions: breathing, blood pressure, homeostasis, and so on.

The midbrain or limbic system was the next part of the brain to evolve, but remained fairly basic until mammals emerged. The midbrain stores memories and emotions, and transmits a lot of messages to the hindbrain. When an elk sees a rival elk, for example, the limbic system creates a feeling of fear, then releases messages to the hindbrain to say "get ready for flight or fight". The hindbrain then releases adrenaline, and the rest is a blur.

The forebrain or cortex is where primates, especially humans, got dealt the royal flush. Decision making, processing of visual information, higher thought, and problem solving is handled by the latest evolution of the brain. And herein lies another secret seed of major depression.

Let's say you - a relatively healthy early human cave-person - decide to go for a walk in the forest, looking for fruit or a cheeseburger or whatever cave-people ate. Suddenly, here's a wild pig, and now he's gored you in the stomach. What would happen naturally? You would undergo a stress response. This response has several familiar flavours:

You hunker down to preserve energy and limit additional pain - just like psychomotor retardation.

You instantly regret all the events that led up to your goring - just like grief.

Your appetite and sex drive diminish as you start to die - just like anhedonia.

Do these symptoms ring a bell?

The Neurosurgical Solution

If you sit there and think obsessively about starving African children, your body does the same thing as if you were just gored by a pig. Your rumination over sad thoughts tells your body that these sad things are really happening. Your super smart cortex conjures a complex story of woe, and your midbrain and hindbrain can't differentiate the story from reality.

This is an overly simplistic explanation of depression. So what would be an overly simplistic response?

This is called a cingulotomy. It's a real thing surgeons actually do to desperately depressed people. A singular bundle cut between the cortex and limbic system significantly reduces depression. This radical procedure is reserved for those who have tried every drug and every therapy and electroshock intervention and every combination thereof, and they still end up in hospital every two months with slashed wrists. Amazingly, with a cingulotomy, they get better.

Sounds great! Are there any other side effects? It's not like it's a frontal lobotomy; you're only disconnecting the limbic system from the cortex so your abstract sad thoughts no longer influence your actual emotions. But if you lose your abstractly miserable thoughts, then you lose your have abstractly pleasurable thoughts too. All thoughts and emotions become disconnected.

But remember, a candidate for a cingulotomy is someone whose every moment of life is emotional anguish. If a man who's on fire cries out for help, you wouldn't tell him that extinguishing the flames would deprive him of warmth. He has no capacity to feel warmth - to generate pleasurable thoughts - so by any definition it's an improvement.

It's definitely a last resort, but neurosurgery is a ray of light for someone whose options are a lifetime of pain or suicide.

Ah, But Hormones!

What have hormones got to do with depression?

There is one important domain of hormones called thyroid hormones. These deal with tasks like metabolism and keeping your body warm. When you have a deficiency in thyroid hormones (hypothyroidism) lots of things happen, including a descent into major depression. There's also a lovely autoimmune disease called Hashimoto's disease, marked by problems secreting thyroid hormones and, you guessed it, major depression. The best estimates suggest 20% of major depressions are actually cases of undiagnosed hypothyroidism.

The next domain of hormones includes oestrogen and progesterone. Women, known for their haphazard and blatant production of these hormones, have twice the risk of developing depression than men. A woman's highest risk for developing depression occurs when oestrogen production fluctuates the most: after giving birth, around the time of her period, and around the time of menopause. Like so many other clues in this dastardly whodunnit, this screams biology.

The Sociology of Women

There are many other schools of thought relating to women's elevated vulnerability for major depression - such as the sociological stance. This suggests that women generally have less control over their environment, and of course lack of control is associated with depression.

Another school focuses on emotionality: women tend to ruminate more on upsetting things. If you take a woman who's just had a fight with a close friend, what is she going to do? Given a choice of many questionnaires, women tend to want to fill out a questionnaire about their friend, how they met, if the friend has a good marriage, and all aspects of the friendship that might have led to the argument.

Contrast this to men, who are more likely to choose questionnaires on trivia and unrelated topics, showing they tend to ruminate less on average. This much is solid science.

What's not solid science is the speculation that if you ruminate on bad feelings then you're more prone to depression. That's an emotional regulation argument and it's difficult to measure or validate.

So let's not dwell on this unknowable psychological path - and instead come back to the biological basis of women being more vulnerable to depression than men.

Stress Hormones

Childbirth, periods and menopause are very obvious biological signposts, and there's a lot of literature about the relationship between depression and the female hormones, oestrogen and progesterone. Most importantly, there are clues in the ratio of oestrogen to progesterone. After giving birth, levels of these hormones jump around like a rat on a tramp. They have significant effects on the signalling of the neurotransmitters we discussed earlier. So regardless of what's happening at the nuts and bolts level (neuroanatomy), oestrogen and progesterone have their effects at the neurochemical level.

The final class of hormones to consider are stress hormones. No, not adrenaline, that's yesterday's news! There's a much more important stress hormone out there, to which Robert Sapolsky has dedicated the last 30 years of his life, a class of hormones called glucocorticoids. These are secreted by your adrenal gland in times of stress. The human version is called hydrocortisol (aka cortisol) although other species have their own version.

Half of all people with major depression show significantly elevated levels of hydrocortisol. There's certainly something out of whack with the regulation of this stress hormone during depression.

What's that about? Let's remember that major depressives' bodies are undergoing a massive stress response. There's a huge emotional battle going inside their heads. It's clear that if you get exposed to a lot of glucocorticoids, you're at risk for depression. Epidemiologically you can see this, because statistically, before someone's first major depressive episode, something awfully stressful occurs. Then they just stay sad and don't bounce back.

If you do come out the other side, you're at no more at risk for depression than anyone else. If you bounce back from a second major bad event, you're still safe. The problem occurs somewhere around the fourth or fifth major stressor. At that point, the stress response starts cycling on its own, and you no longer even need an external life stressor to trigger another episode.

This means that major life stress can predispose you for depression.

I Need More Evidence!

Of course you do. How about Cushing's disease? Here, people secrete lots of corticoids, then often fall into major depression. Likewise, there are bunch of diseases that require people to be treated with lots of glucocorticoids, and the side effect is that they fall into major depression. What are these damned glucocorticoids doing? They leave you low in dopamine, and then you're right back in the domain of depression.

So far we've covered brain chemistry, brain structure, and hormones. But if that's all you know, you're going to be pitifully bad at helping someone with depression, because all of this knowledge winds up being effective for treating maybe 30-40% of depressives. The rest of the major depressives do not respond to drugs therapies. Fixing the biology is not enough.

The Psychology of Depression

Psychology is a critical piece of the jigsaw puzzle, which we'll tip out onto the floor by talking about Sigmund Freud for a bit. Freud asked why some people bounce back from sadness, and some don't; the latter he diagnosed with melancholia.

What's the difference between mourning and melancholia? Freud came up with a good model. According to Freud, you have mixed feelings for all people out there. You love them, hate them, resent them, hope for them, pity them, envy them, and wish they would pay you a bit more attention.

When you lose a loved one, you feel grief. You focus on the love you had and grieve that you lost them and all the positive associations. You put the negative feelings aside and mourn the loss of the good stuff.

Contrast this to melancholia, where you're unable to put the negative feelings in the background. You haven't just lost someone you loved, but someone you hated, envied, pitied, and everything else.

Isn't that better? No, because you've also lost the opportunity to ever make things right and come to peace with that person. Knock knock! Who's there? It's an unending sense of guilt for never making things right with the deceased! And who did guilt brought with him? It's shame! Shame for feeling hatred and jealousy and contempt for someone who's now dead.

Depression is aggression turned inward. Your lost loved one is not there to have an argument with, you can no longer pound on the door and have it all out with them. You've lost that opportunity forever, and all you can do is internalise that, be angry at yourself, and thus the aggression turns inwards. No wonder you're not feeling pleasure, have too many stress hormones, and don't want to get out of bed.

But how do you reconcile Freudian theory with neurochemistry? What does the oestrogen:progesterone ratio have to do with love:hate ratios? It feels intuitive but you can't quite science it properly. This is the problem with the best parts of Freud.

Instead, you have to turn over to experimental psychology. What makes psychological stressors stressful?

Plenty of literature now shows that for the same external misery, you undergo a greater stress response and are more at risk for stress-related disease when any of four factors occur:

You don't have any outlets for the frustration caused by the stressor

You feel like you have no control over the stressor

You feel unable to predict when the stressor will occur

You don't have social support or a shoulder to cry on

This is what psychological stress is all about - and depression is the pathological extreme of such stress.

Major Depression is Learned Helplessness

What happens if an abominable gull flaps into your house each morning and pecks your skull?

You shoo it away and get on with your breakfast. It's a bad situation, but you will recover, and you may even shut the window so it can't happen again. The major depressive, on the other hand, will sit there morning after morning and simply accept that their life now involves a daily skull-pecking.

Human depression is cognitive distortion. A major depressive will be unable to see past a bad situation. They feel they have no control, that they are always hopeless and helpless. This is the psychology of depression.

Compare this to what a major depressive sees:

So you have two viewpoints: biological evidence vs psychology theory surrounding loss and lack of control.

One of the most reliable findings in the whole epidemiology of depression is that if you lose a parent to death at age 10 or younger, for the rest of your life you're at greater risk of major depression. This makes perfect sense. For our first 10 years, we are learning about cause and effect. We learn whether this is a world over which we have any efficacy or control. When a parent dies while we're still learning about the world, we learn in a big way that traumatic things happen over which we have no control. This brings us closer to the edge of the learned helplessness cliff for the rest of our lives.

So how do you marry these biological and psychological viewpoints? If you've got a keen eye, you may have noticed a common word used by the two viewpoints: stress. Stress is the intersection.

Major depression is a genetic disorder. This means it has some degree of heritability, it tends to run in families, and it runs more reliably in closer genetic relationships. In identical twins, if one twin gets depression, the other twin has a 50% chance of getting it too. In non-identical twins or regular siblings, this chance drops to 25%. In half-siblings the chance is 8%, and in a random stranger it's just 2%. This all tells you depression is a genetic (and therefore a biologically predisposed) disorder.

This also reveals that even if you have a genetic predisposition of 50%, you also have a 50% chance of not getting depressed. So while genetics play a key role, it's no more than all the environmental components combined. Genes and other causes of major depression are not about inevitability, they are about vulnerability.

What Creates Vulnerability to Depression?

In the early 21st century, researchers scienced a particular gene that's relevant to serotonin and whether you get major depression. This gene has two possible flavours, and we all have it, in either one flavour or the other. The researchers hypothesised that the vulnerable version of the gene (type V) automatically predisposes you to major depression, while the other offers relative protection from the illness (type P).

The ensuing study examined the genetic makeup of 17,000 kids growing up here in New Zealand and produced arguably the most important paper in modern biological psychiatry. Year after year, the researchers watched the kids grow up, then tracked who among them got depression, and then sought out genetic testing to see who possessed what type of the gene.

Contrary to their hypothesis, they found the presence of type V or type P actually didn't affect the risk of participants developing depression in their lifetime. Both type V and type P versions of the gene showed the same correlation with depression. That was, unless participants had a history of exposure to major stressors, like parental divorce, abuse, or the death of a close family member. That's when the genetic component kicked in.

As people with the type P gene were exposed to more and more life stressors, their instances of major depression rose. However, as people with the type V gene suffered an increasing number of life stressors, their the likelihood of major depression rose by 30 times that of the other group.

This single gene mutation has a significant effect on how readily we recover after major life traumas, and subsequently go on to develop major depression.

The Final Piece of The Story

Tying it all neatly back into a lovely little bow of despair, it turns out the aforementioned hydrocorticoids actually regulate the functioning of this gene. Suddenly we have a way of taking the world of psychology and integrating it with the biology, and everything fits neatly into place. This is where the field of major depression research rests today.

What do we know about major depression? We know depression hinges on stress and the intersection of psychological and biological factors, combined with childhood as a critical time for vulnerability to becoming predisposed.

What else do we know about major depression? We know depression is not solved by barking: "Just harden up! We all get depressed!" Depression is as biological as diabetes.

Depression is all around us. Yet so is this corrosive inhibition, compounded by the stigmatised embarrassment we have with the term psychiatric disease.

Sapolsky says one of the greatest things a disease researcher can hope for is that a powerful politician's loved one is struck down by their disease, because they'll set up a foundation and get research funding and a cure will be forthcoming.

But this is not the case for psychiatric disorders. They're the ones people don't talk about. Depression is commonly seen as weak and shameful and should be kept secret, let alone being encouraged to seek a medicated treatment.

Amid this screaming biology of depression, in a world where we use Facebook to paint a picture of our perfect lives, this disease is one we don't admit to, as if we are ashamed to reveal we are anything other than round-the-clock happy. But suppression is the worst thing we can do. To deny we are sick is to deny any chance of getting better.